Disease relevance of PMP22

• Charcot-Marie-Tooth disease type 1A (CMT1A) is an autosomal dominant neuropathy that can be caused by dominant point mutations in PMP22 which encodes a peripheral nerve myelin protein [1].
• Dejerine-Sottas disease, also called hereditary motor and sensory neuropathy type III (HMSNIII), is a severe, infantile onset demyelinating polyneuropathy syndrome that may be associated with point mutations in either the PMP22 gene of the P0 gene [2].
• Amplitude of CMAPs was correlated significantly with distal muscle strength in PMP22 duplication, MPZ mutations and Cx32 mutations, while MCV slowing was not, indicating that clinical weakness results from reduced numbers of functional large axons, not from demyelination [3].
• Tetraspan myelin protein PMP22 and demyelinating peripheral neuropathies: new facts and hypotheses [4].
• Peripheral myelin protein 22 (PMP22) is expressed by Schwann cells in the peripheral nervous system (PNS), and mutations affecting the PMP22 gene are associated with hereditary motor and sensory neuropathies [5].

Psychiatry related information on PMP22

• In family 1, a 6-year-old girl and her 5-year-old brother were diagnosed with mental retardation, short stature, dysmorphic features, and Charcot-Marie-Tooth disease type 1A (CMT1A) [6].
• Developing decision support systems for integrated coastal management in the tropics: is the ICM decision-making environment too complex for the development of a useable and useful DSS [7]?
• CONCLUSION: The authors conclude that CMT1A patients with normal peripheral hearing have auditory processing abilities that were not indicative for an auditory processing disorder [8].

High impact information on PMP22

• Mutations in the gene encoding the PML nuclear body protein Sp110 are associated with immunodeficiency and hepatic veno-occlusive disease [9].
• PMP22 Thr(118)Met: recessive CMT1 mutation or polymorphism [10]?
• Duplications of a chromosome Xp21 locus DSS (Dosage Sensitive Sex reversal) are associated with male to female sex reversal [11].
• The Charcot-Marie Tooth disease type 1A (CMT1A) duplication and hereditary neuropathy with liability to pressure palsies (HNPP) deletion are reciprocal products of an unequal crossing-over event between misaligned flanking CMT1A-REP repeats [12].
• As the deleted DNA region includes the coding region for a peripheral myelin gene (PMP22), we used single strand conformation analysis to examine this gene for mutations in the non-deleted HNPP family [13].

Chemical compound and disease context of PMP22

• The TMP amino acid sequence bears high homology to the growth arrest specific protein PMP22/GAS-3, which is involved in several human peripheral neuropathies [14].
• METHODS: Nerve conduction study of upper limbs was investigated in 19 chronic inflammatory demyelinating polyneuropathy (CIDP) patients, 25 anti-myelin-associated glycoprotein/sulfated glucuronyl paragloboside antibodies (MAG/SGPG) CDP patients, 13 Charcot-Marie-Tooth disease type 1A (CMT1A) patients and 22 controls [15].
• There is no treatment for Charcot-Marie-Tooth disease 1A (CMT1A), but ascorbic acid (AA) is efficacious in the transgenic mouse model [16].
• The mutation results in a serine to threonine amino acid substitution at residue 72, which is a hot spot for mutation in human PMP22, leading to the peripheral neuropathy Dejerine-Sottas syndrome [17].
• Tissue culture studies demonstrated that SR13/PMP-22 mRNA is induced in NGF treated PC12 but not in C6 glioma cell lines grown under experimental conditions that stimulated cell growth arrest [18].

Biological context of PMP22

• Usually, CMT1A is caused by the duplication of a 1.5-megabase (Mb) region on chromosome 17p11.2-p12 containing PMP22 [1].
• Evidence for a recessive PMP22 point mutation in Charcot-Marie-Tooth disease type 1A [1].
• We have identified a severely affected CMT1 patient who is a compound heterozygote for a recessive PMP22 point mutation, and a 1.5 Mb deletion in 17p11.2-p12 [1].
• PMP22 and EMPs are expressed in many tissues, and functions in cell growth, differentiation, and apoptosis have been reported [19].
• Here, we demonstrate for the first time that P0 and PMP22 proteins form complexes in the myelin membrane, as shown by coimmunoprecipitation experiments, and that glycosylation is not involved in mediating these interactions [20].

Anatomical context of PMP22

• PMP22 is most highly expressed in peripheral nerves, where it is localized in the compact portion of myelin [19].
• In transfected cells, P0 and PMP22 are recruited and colocalize at the apposed plasma membranes of expressors as shown by confocal microscopy [20].
• Although the precise biological role of PMP22 remains to be discovered, our results support the hypothesis that this protein serves multiple functions in Schwann cells [21].
• On the other hand, disease-related missense mutations within transmembrane domains of PMP22 disturb intracellular protein trafficking leading to accumulation of the mutant protein in the endoplasmic reticulum/Golgi compartment [4].
• PMP22 normally is expressed at high levels in Schwann cells of the peripheral nervous system and is suggested to function as a structural protein of the myelin sheath [22].

Associations of PMP22 with chemical compounds

• Peripheral Myelin Protein-22 (PMP22) is a membrane glycoprotein which represents up to 5% of total protein in myelin of peripheral nerves [21].
• RESULTS: Nucleotide 159 of PMP22 showed an A-to-T heterozygous mutation, predicted to cause an aspartate-to-valine substitution at codon 37 in the first extracellular loop of the protein [23].
• The results suggest an inverse pattern of expression for the two homologs, TMP expression being high during cell proliferation and PMP22 expression being high during growth arrest [14].
• As shown for the animal model of globoid cell dystrophy, it is conceivable that increased expression of MHC class II molecules in CMT1 and HNPP accelerates nerve pathology [24].
• A 10-year-old boy was identified with a point mutation in PMP22, which resulted in the substitution of cysteine for serine in a putative transmembrane domain of PMP22 [25].

Regulatory relationships of PMP22

• Genetic analysis identified the boy as a heterozygote for both a peripheral myelin protein 22 (PMP22) duplication and a mutation in the lipopolysaccharide-induced-tumour-necrosis-factor-alpha-factor (LITAF) gene, whereas each parent only had one mutated CMT gene [26].

Other interactions of PMP22

• Axonal features of diminished amplitudes of compound muscle action potentials (CMAPs), axonal loss, axonal sprouting and neuropathic muscle wasting all changed as disease advanced, especially in PMP22 duplication and Cx32 mutations [3].
• Epithelial membrane protein-2 and epithelial membrane protein-3: two novel members of the peripheral myelin protein 22 gene family [5].
• Dejerine-Sottas disease (DSD), also called hereditary motor and sensory neuropathy type III (HMSNIII), is a severe, infantile-onset demyelinating polyneuropathy syndrome that may be associated with point mutations in either the PMP22 gene, PO gene, EGR2 gene or the PRX gene (for the recessive form) [27].
• To date, a genetic defect in one of these genes has been identified in over 1,000 unrelated patients manifesting a wide range of phenotypes, i.e., Charcot-Marie-Tooth disease type 1 (CMT1) and type 2 (CMT2), Dejerine-Sottas syndrome (DSS), hereditary neuropathy with liability to pressure palsies (HNPP), and congenital hypomyelination (CH) [28].
• Our results demonstrate that PMP22, P0 protein, and myelin basic protein are present in compact myelin of all patients examined [21].

Analytical, diagnostic and therapeutic context of PMP22

• The peripheral myelin proteins P0 and PMP22 are associated in preparations of compact myelin and in cell cultures coexpressing both molecules [29].
• Determination of gene dosage at the PMP22 and androgen receptor loci by quantitative PCR [30].
• We could prove expression of PMP22 by reverse transcriptase-polymerase chain reaction (RT-PCR) and discovered an unusual PMP22 transcript in these tumor cell lines [22].
• Molecular diagnosis of PMP22-associated neuropathies using fluorescence in situ hybridization (FISH) on archival peripheral nerve tissue preparations [31].
• These alterations were seen to a lesser extent in PMP22 deletion or point mutation xenografts and were not observed in controls [32].

References